Oncolytic adenoviruses: a game changer approach in the battle between cancer and the immune system.

Introduction: Oncolytic adenoviruses are among the most studied oncolytic viruses because of their tumor selectivity, safety, and transgene-delivery capability. With a growing number of different immunotherapies against cancer, the extraordinary immunogenicity of the adenovirus has emerged as a differentiating strength. Enabling T-cell related therapies with oncolytic adenoviruses appears a promising approach due to its inherent ability to elicit responses from the adaptive immune compartment.

Areas covered: These viruses have successfully enhanced both adoptive T-cell therapies and immune-checkpoint therapies. Oncolytic viruses induce several effects at the tumor and on the systemic level that help to circumvent current limitations of T-cells and related therapies, such as T-cell trafficking, tumor immune suppressivity and antigen spreading.

Expert opinion: Taking into account the multitude of possibilities of treating cancer with immunotherapies, learning to optimize the combinations and administration strategies of these drugs, could lead to durable responses in patients with currently incurable cancers.     

Oncolytic measles virus strains as novel anticancer agents

Introduction: Replication-competent oncolytic measles virus (MV) strains preferentially infect and destroy a wide variety of cancer tissues. Clinical translation of engineered attenuated MV vaccine derivatives is demonstrating the therapeutic potential and negligible pathogenicity of these strains in humans.

Areas covered: The present review summarizes the mechanisms of MV tumor selectivity and cytopathic activity as well as the current data on the oncolytic efficacy and preclinical testing of MV strains. Investigational strategies to reprogram MV selectivity, escape antiviral immunity and modulate the immune system to enhance viral delivery and tumor oncolysis are also discussed.

Expert opinion: Clinical viral kinetic data derived from noninvasive monitoring of reporter transgene expression will guide future protocols to enhance oncolytic MV efficacy. Anti-measles immunity is a major challenge of measles-based therapeutics and various strategies are being investigated to modulate immunity. These include the combination of MV therapy with immunosuppressive drugs, such as cyclophosphamide, the use of cell carriers and the introduction of immunomodulatory transgenes and wild-type virulence genes. Available MV retargeting technologies can address safety considerations that may arise as more potent oncolytic MV vectors are being developed.     

Oncolytic virotherapy for renal cell carcinoma: a novel treatment paradigm?

Introduction: Despite the development of novel targeted therapies, metastatic renal cell carcinoma (mRCC) remains an incurable disease. The known responsiveness of mRCC to immunotherapy and the molecular aberrations characteristic of this disease make it an attractive malignancy for treatment with oncolytic viruses (OVs), as these agents are capable of usurping common oncogenic signaling pathways and generating anti-tumor immune responses.

Areas covered: The current evidence to support the use of oncolytic virotherapy against mRCC is discussed with emphasis on the molecular and immunological features of this disease that may be exploited by these biologic agents. Furthermore, the mRCC tumor microenvironment will be detailed to highlight the many OV restrictive factors that exist, which will need to be overcome to realize the full potential of oncolytic virotherapy for this disease.

Expert opinion: Preclinical development of OVs for the treatment of mRCC should utilize syngeneic immunocompetent animal models to allow for the assessment of both the anti-viral and anti-tumor immune response generated by these agents in addition to human xenograft models. Furthermore, rationale combination therapies incorporating currently approved mRCC-targeted therapies should be explored as these approaches hold the greatest potential for translating OVs into the clinical arena for use against this disease.     

High-dose VitC plus oncolytic adenoviruses enhance immunogenic tumor cell death and reprogram tumor immune microenvironment

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In vivo and in vitro distribution of type 5 and fiber-modified oncolytic adenoviruses in human blood compartments

Abstract

Background. Successful tumor targeting of systemically administered oncolytic adenoviruses may be hindered by interactions with blood components.

Materials and methods. Blood distribution of oncolytic adenoviruses featuring type 5 adenovirus fiber, 5/3 capsid chimerism, or RGD-4C in the fiber knob was investigated in vitro and in patients with refractory solid tumors.

Results. Virus titers and prevalence in serum of patients increased over the first post-treatment week, suggesting replication. Detection of low virus loads was more sensitive in blood clots than in serum, although viral levels > 500 viral particles/mL did not differ significantly between both sample types. While adenovirus bound to erythrocytes, platelets, granulocytes, and peripheral blood mononuclear cells in vitro, the virus was mainly detectable in erythrocytes and granulocytes in cancer patients. Taken together with a temporary post-treatment decrease in thrombocyte counts, platelet activation by adenovirus and subsequent clearance seem likely to occur in humans. Fiber modifications had limited observed effect on virus distribution in blood cell compartments. Neutrophils, monocytes and cytotoxic T lymphocytes were the major leukocyte subpopulations interacting with adenoviruses.

Conclusion. Serum and blood clots are relevant to estimate oncolytic adenovirus replication. Insight into viral interactions with blood cells may contribute to the development of new strategies for tumor delivery.     

Prevention of restenosis after coronary angioplasty: towards a molecular approach?

Summary— Restenosis after coronary angioplasty, the main limitation of interventional cardiology, remains an unsolved issue. The failure to-date of all pharmacological attemps at prevention has prompted the development of alternative strategies. A mechanistic approach to the problem of restenosis is based on the assumption that creating a more satisfactory acute angioplasty result would reduce the development of restenosis. With the exception of coronary stenting, however, none of the new angioplasty devices have convincingly reached this goal. Furthermore, recent advances in the field of vascular biology have opened new avenues for a molecular approach of restenosis. Better understanding of the pathophysiology of restenosis, in conjunction with high-pace development of catheter, polymer, and virus technologies, provide opportunities to deliver agents — drugs, genes, or antisense oligonucleotides — locally, at the site of angioplasty to interfere specifically with the restenosis process. Some of these molecular strategies are currently being investigated in animal models. Clinical application of a molecular approach to prevent restenosis, however, will require close collaboration between physicians, molecular biologists, and bio-engineers.     

Beyond cancer cells: Targeting the tumor microenvironment with gene therapy and armed oncolytic virus

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Reshaping the Immune Microenvironment by Oncolytic Herpes Simplex Virus in Murine Pancreatic Ductal Adenocarcinoma

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Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature

Introduction: Immunotherapy, in its entirety, represents a promising field at the forefront of cancer. Treatment with potent cytokine IL-12 has provided science with many challenges, but has also demonstrated promise as therapeutic strategy in ovarian cancer.

Areas covered: This review examines the anti-tumor mechanism of action of IL-12 and the development of IL-12 as a potential therapeutic option in a variety of malignancies. It also reviews the immunogenicity of ovarian cancer and covers preclinical and clinical trials that have contributed to the advancement of IL-12 as a potential therapy for ovarian malignancy. The obstacles that researchers have overcome and currently face regarding the use of IL-12 in clinical ovarian cancer trials are also discussed.

Expert opinion: IL-12, as a therapeutic modality, is mechanistically logical and shows great promise in preclinical trials. Further clinical studies are warranted to optimize the potential of IL-12 as a treatment strategy for ovarian cancer.     

Oncolytic herpes simplex virus therapy for malignant glioma: current approaches to successful clinical application

Introduction: With the approval of talimogene laherparepvec (T-VEC) for advanced malignant melanoma, virotherapy using oncolytic herpes simplex virus (oHSV) is now emerging as a viable therapeutic option for cancer patients, including malignant gliomas.

Areas covered: This review summarizes the most recent literature to provide cutting-edge knowledge about preclinical and clinical development of oHSV therapy for malignant gliomas, presenting current approaches to overcome obstacles to successful clinical application of oHSV in neuro-oncology.

Expert opinion: Current strategies to improve the efficacy of oHSV therapy include engineering new viruses, modulation of innate and adaptive immune responses, combination with other treatments, and developing new oHSV delivery. All of these could rapidly be translated into clinical investigations, following several clinical trials that are currently ongoing.     

Adenoviral virotherapy for malignant brain tumors

Glioblastoma multiforme is the most common form of primary brain cancer. In the past decade, virotherapy of tumors has gained credence, particularly in glioma management, as these tumors are not completely resectable and tend to micro-metastasize. Adenoviral vectors have an advantage over other viral vectors in that they are relatively non-toxic and do not integrate in the genome. However, the lack of coxsackie and adenovirus receptors on surface of gliomas provides for inefficient transduction of wild-type adenoviral vectors in these tumors. By targeting receptors that are overexpressed in gliomas, modified adenoviral constructs have been shown to efficiently infect glioma cells. In addition, by taking advantage of tumor-specific promoter elements, oncolytic adenoviral vectors offer the promise of selective tumor-specific replication. This dual targeting strategy has enabled specificity in both laboratory and pre-clinical settings. This review examines current trends in adenoviral virotherapy of gliomas, with an emphasis on targeting modalities and future clinical applications.     

Oncolytic-adenovirus-expressed RNA interference for cancer therapy

Importance of the field: RNA interference (RNAi) has generated considerable excitement for its potential cancer therapeutic applications. Because of the difficulties in delivering a large amount of siRNA to cancer cells and the short half-life of siRNA, it is important to choose an efficient delivery system for transduction of siRNA into target cells. Oncolytic adenovirus offers a better platform by virtue of its high transfection efficiency and selective replication in cancer cells.

Areas covered in this review: This review focuses on the synergism between oncolytic adenovirus and siRNA antitumor responses, and discusses recent progresses in oncolytic-adenovirus-expressed siRNA.

What the reader will gain: siRNA-expressing oncolytic adenovirus can generate a significantly enhanced antitumor effect through gene knockdown and viral oncolysis.

Take home message: Due to its potency and target specificity, using siRNA delivery by oncolytic adenovirus has generated much excitement and will open new avenues for treatment of human cancer.     

携带Pdcd5基因的三调控增殖性腺病毒的构建及鉴定

本研究旨在构建一种表达pdcd5基因的三调控增殖性腺病毒。应用DNA重组技术将pdcd5cDNA插入三调控条件增殖性腺病毒SG600的E3区,SG600病毒系统是运用人端粒酶反转录酶基因启动子（hTERTp）和缺氧反应元件（HRE）分别调控病毒复制必须基因E1a和E1b的表达,去除E1a基因CR2区中24个核苷酸而构建成的靶向肿瘤细胞增殖的病毒系统。采用酶切及PCR鉴定并筛选重组成功的质粒。荧光显微镜下观察带增强型绿色荧光蛋白（EGFP）基因的重组腺病毒SG611—EGFP对白血病细胞系的感染效率。实时定量PCR检测感染重组腺病毒SG611．pdcd5的K562细胞pdcd5的表达水平。结果显示,构建的se611-pdcd5病毒能扩增出hTERTp、HRE、pd—cd5基因以及腺病毒骨架和11型纤突结基因序列。SG611-EGFP对白血病细胞系K562和MEG-01的感染效率均能达到70％以上。感染SG611-pdcd5的K562细胞pdcd5的表达水平较SG611空载体和携带pdcd5的非增殖性腺病毒（Ad-pdcd5）明显增加（P〈0．001）,其表达水平随感染复数增加而升高。结论：成功构建了三调控增殖性腺病毒SG611-pdcd5,后者能高效感染白血病细胞系并高效表达pdcd5,为进一步运用pdcd5靶向肿瘤细胞进行基因治疗的研究提供了基础。     

RASONs: a novel antisense oligonucleotide therapeutic approach for asthma

Inhalation based approaches enable the local delivery of antisense oligonucleotides (ASONs) to the respiratory tract and thus facilitate the ability of ASONs to target and modulate the activity of discordantly expressed respiratory disease genes. Studies involving EPI-2010, a respirable antisense oligonucleotide (RASON), targeting the adenosine A₁ receptor, a G-protein-coupled-receptor (GPCR) that plays an important role in the aetiology of asthma, demonstrate that ASON therapeutics can be delivered directly to the lung as an aerosol. EPI-2010 has been shown to inhibit adenosine A₁ receptor expression and significantly improve allergen-induced airway obstruction and bronchial hyper-responsiveness in animal models of human asthma. Absorption, tissue distribution, metabolism and excretion (ADME) and safety studies of aerosolised EPI-2010 suggest that phosphorothioate RASONs can be delivered to target respiratory tissues in low, safe, efficacious and long-acting doses. This supports the concept that RASONs offer the potential to address a variety of respiratory targets including those for which approaches employing systemic distribution and systemic bioavailability of the therapeutic agent may be undesirable. In addition, our studies with EPI-2010 indicate that the RASON approach may represent a technology that is uniquely positioned to address the challenges of the post-genome era in respiratory drug discovery, since it enables simultaneous in vivo target validation and antisense therapeutic discovery in an accelerated timeframe.     

Viral gene therapy for breast cancer: progress and challenges

Introduction: Breast cancer is the most common cancer in women all over the world. Furthermore, up to one third of breast tumors develop metastases that are resistant to standard therapies. Gene therapeutic strategies have been developed in order to specifically target cancer cells either directly or through the stimulation of antitumor immunity.

Areas covered: This review describes the therapeutic strategies that are currently under development to treat this disease using engineered viral vectors including: adenovirus, adeno-associated virus, lentivirus, poxvirus, reovirus, baculovirus, herpesvirus and oncolytic viruses. Advantages and disadvantages of these multiple gene therapy platforms are discussed in detail.

Expert opinion: Metastatic breast cancer is a perfect candidate for gene therapy approaches due to the presence of several tumor antigens and the aberrant expression of many molecular pathways. Oncolytic vectors are able to attack tumor cells while sparing normal cells and their activity is often enhanced by the administration of chemotherapy. However, more efforts are needed in order to reduce toxicity and to achieve better transduction efficiency. Improved preclinical models and a more critical patient selection for clinical trials, along with advances in gene therapy regulations, will surely facilitate the evolution of gene therapy for the treatment of metastatic breast cancer.     

具有野生型活性和新活性的小鼠白介素12融合基因的构建与表达

天然白介素(IL)12是一种异二聚体分子,其工程产品只能在真核细胞内表达,因而产量低,造价高,限制了临床应用。根据融合蛋白的原理,结合IL-12本身的结构特点进行推断,若将IL-12的二亚基(p35/p40)适当改造和融合,其产物可能同样地表达野生型IL-12的活性,这将为在原核表达系统内表达融合蛋白提供先决条件。将p40亚基cDNA中编码Ig-样区域的序列缺失,残余部分与p35亚基的cDNA3’端通过连接序列连接,构成融合IL-12 cDNA(fmIL-12C)。当此融合基因克隆人真核表达载体pMT/EP后在CHO细胞内表达,其产物具有野生型IL-12的活性,即刺激活化淋巴母细胞增殖。与此同时,融合IL-12的cDNA的表达使CHO细胞发生十分明显的形态变化,提示融合IL-12可能具有一些新活性。对此融合基因进一步改造及在原核系统内表达的可能性也进行了讨论。